Osteomalacia (Adult Rickets)

1. Clinical Overview

Summary

Osteomalacia is a metabolic bone disease characterised by defective mineralisation of the osteoid matrix in adults, resulting in the accumulation of unmineralised or inadequately mineralised bone. The term derives from Greek: "osteo" (bone) + "malacia" (softening). In children with open growth plates, the identical pathophysiological process causes Rickets, affecting both the growth plate and bone mineralisation. [1,2]

The hallmark of osteomalacia is the development of "soft bones" due to inadequate Calcium and Phosphate availability for hydroxyapatite crystal formation, most commonly caused by Severe Vitamin D Deficiency. This results in bones with normal collagen matrix (osteoid) but deficient mineral content, compromising structural integrity. [3]

Clinically, osteomalacia presents with a characteristic triad: diffuse bone pain, proximal myopathy (manifesting as a waddling gait), and bone tenderness on palpation. Biochemically, it is defined by elevated alkaline phosphatase (ALP), low or low-normal serum Calcium, low serum Phosphate, and markedly reduced 25-hydroxyvitamin D levels. The elevated ALP reflects increased but ineffective osteoblast activity attempting to mineralise defective osteoid. [4,5]

Clinical Pearls

Osteomalacia vs Osteoporosis: This is the classic examination distinction and a frequent source of clinical confusion.

• Osteoporosis: "Brittle bones" with reduced bone mass but normal mineralisation of existing bone. Blood tests including ALP are NORMAL. Typically painless until fracture occurs. DEXA scan shows low bone mineral density.
• Osteomalacia: "Soft bones" with defective mineralisation despite normal or increased bone volume. ALP is characteristically ELEVATED. Persistent bone pain even without fracture. DEXA may show normal or even high bone density (unmineralised osteoid is registered).

The Proximal Myopathy and "Waddle": Vitamin D receptors (VDR) are abundantly expressed in skeletal muscle as well as bone tissue. Severe deficiency causes a prominent Proximal Myopathy affecting hip girdle and shoulder girdle muscles. Patients struggle to rise from a chair without using their arms, cannot climb stairs normally, and walk with a characteristic waddling gait due to gluteal weakness. This myopathy often leads to misdiagnosis as polymyositis, polymyalgia rheumatica, or neurological disease. [6]

Pseudofractures (Looser's Zones): The pathognomonic radiological sign of osteomalacia. These are radiolucent bands perpendicular to the cortex, representing stress fractures filled with unmineralised osteoid at sites of repetitive mechanical stress. Common locations include femoral neck, pubic rami, ribs, scapula, and proximal ulna. Named after Swiss physician Emil Looser who described them in 1920. Also called "Milkman's fractures" or "stress fractures". [7]

Bone Pain Distribution: Unlike the acute, focal pain of fracture, osteomalacia causes persistent, diffuse, deep aching bone pain. Patients often describe it as "my bones feel tired" or "a deep ache that never goes away". Pain is typically worse with weight-bearing and improves with rest. The sternum and anterior tibial surface are particularly tender to pressure. [8]

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2. Epidemiology

Global Prevalence

Osteomalacia remains a significant global health problem despite being entirely preventable and treatable. The true prevalence is difficult to establish as the condition is often undiagnosed or misdiagnosed. Vitamin D deficiency (defined as serum 25(OH)D less than 50 nmol/L) affects approximately 1 billion people worldwide, though only a subset develop clinical osteomalacia. [9,10]

Demographics and Risk Groups

High-Risk Populations:

1. Elderly and Institutionalised Individuals:

   • Reduced skin synthesis (7-dehydrocholesterol decreases with age)
   • Limited outdoor activity and sunlight exposure
   • Reduced dietary intake
   • Prevalence of vitamin D deficiency in nursing home residents approaches 75-100% in some studies [11]

2. Ethnic Groups with Darker Skin Pigmentation:

   • Increased melanin reduces UV-B penetration and cutaneous vitamin D synthesis
   • Asian, Afro-Caribbean, and Middle Eastern populations living at northern latitudes
   • May require 5-10 times longer sun exposure to synthesise equivalent vitamin D [12]
   • Particularly problematic in Muslim women wearing concealing clothing (hijab/burqa)

3. Malabsorption Syndromes:

   • Coeliac disease: 10-30% have vitamin D deficiency at diagnosis
   • Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
   • Post-bariatric surgery: Particularly after Roux-en-Y gastric bypass
   • Chronic pancreatitis: Reduced fat-soluble vitamin absorption
   • Biliary obstruction: Impaired bile salt delivery to intestine [13]

4. Chronic Kidney Disease (CKD):

   • Loss of renal 1α-hydroxylase activity
   • Cannot convert 25(OH)D to active 1,25(OH)₂D
   • Develops into renal osteodystrophy complex [14]

5. Drug-Induced:

   • Anticonvulsants (phenytoin, carbamazepine, phenobarbital): Induce hepatic CYP450 enzymes, accelerating vitamin D catabolism
   • Tenofovir (HIV treatment): Causes Fanconi syndrome with renal phosphate wasting [15]
   • Adefovir (hepatitis B treatment): Similar mechanism to tenofovir
   • Aluminium-containing antacids: Bind dietary phosphate

6. Dietary:

   • Vegans: Absence of dietary vitamin D (found mainly in animal products)
   • Low calcium intake (less than 700 mg/day)
   • Phytate-rich diets: Binds calcium and phosphate (e.g., unleavened bread, chapattis)

Epidemiological Data

Seasonal Variation

In temperate climates (latitudes above 35°), cutaneous vitamin D synthesis essentially ceases during winter months (November-March in Northern Hemisphere) due to insufficient UV-B radiation. This creates a seasonal nadir in 25(OH)D levels, typically occurring in late winter/early spring. [16]

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3. Aetiology and Pathophysiology

Classification of Causes

Osteomalacia can be classified by mechanism:

3.1 Vitamin D Deficiency or Abnormal Metabolism

Reduced Synthesis:

• Inadequate sunlight exposure (latitude, season, clothing, sunscreen use)
• Skin pigmentation (melanin blocking UV-B)
• Aging (reduced 7-dehydrocholesterol in skin)

Malabsorption:

• Coeliac disease, inflammatory bowel disease
• Post-gastrectomy, post-bariatric surgery
• Pancreatic insufficiency, cholestatic liver disease
• Small bowel resection or bypass

Accelerated Catabolism:

• Anticonvulsant medications (phenytoin, carbamazepine, phenobarbital)
• Rifampicin (induces CYP24A1)

Impaired Activation:

• Chronic kidney disease (loss of renal 1α-hydroxylase)
• Hereditary vitamin D-dependent rickets type I (CYP27B1 mutation)

Vitamin D Resistance:

• Hereditary vitamin D-dependent rickets type II (VDR mutation)

3.2 Hypophosphataemia

Renal Phosphate Wasting:

• Tumor-Induced Osteomalacia (TIO): Phosphaturic mesenchymal tumour secreting FGF23 [17]
• X-Linked Hypophosphataemia (XLH): PHEX gene mutation leading to elevated FGF23 [18]
• Autosomal Dominant Hypophosphataemic Rickets (ADHR): FGF23 gene mutation
• Fanconi Syndrome: Generalised proximal tubular dysfunction
  • Tenofovir, adefovir, ifosfamide, cisplatin, heavy metals
  • Multiple myeloma, light chain disease
  • Wilson's disease, cystinosis, tyrosinaemia
• Hereditary hypophosphataemic rickets with hypercalciuria (HHRH): SLC34A3 mutation

Reduced Intestinal Absorption:

• Aluminium-containing antacids (bind phosphate)
• Phosphate-binding resins

Dietary Deficiency:

• Extreme protein-calorie malnutrition (rare in developed countries)

3.3 Mineralisation Inhibitors

• Bisphosphonates (especially first-generation etidronate): Pyrophosphate analogues
• Fluoride (chronic excess): Direct inhibition of mineralisation
• Aluminium (chronic exposure, especially in dialysis patients)
• Hypophosphatasia: Tissue-nonspecific alkaline phosphatase (TNSALP) deficiency

Molecular Pathophysiology

Normal Bone Mineralisation

Bone mineralisation requires:

1. Adequate calcium and phosphate in extracellular fluid
2. Calcium × Phosphate product exceeding solubility threshold (approximately 4.4 mmol²/L²)
3. Alkaline phosphatase to cleave pyrophosphate (mineralisation inhibitor)
4. Proper osteoid matrix for hydroxyapatite crystal deposition
5. Absence of mineralisation inhibitors

Vitamin D Metabolism Cascade

Skin (UV-B exposure)
    ↓
7-Dehydrocholesterol → Cholecalciferol (Vitamin D₃)
    ↓
Liver (25-hydroxylase/CYP2R1)
    ↓
25-Hydroxyvitamin D [25(OH)D] — Storage form, measured clinically
    ↓
Kidney (1α-hydroxylase/CYP27B1) — Rate-limiting step, stimulated by PTH, inhibited by FGF23
    ↓
1,25-Dihydroxyvitamin D [1,25(OH)₂D] — Active hormone, calcitriol
    ↓
Binds Vitamin D Receptor (VDR) → Nuclear transcription
    ↓
Effects: ↑ Intestinal Ca²⁺/PO₄³⁻ absorption
        ↑ Renal Ca²⁺ reabsorption
        ↑ Bone remodelling
        ↑ Muscle function

Pathophysiological Sequence in Vitamin D Deficiency

Stage 1: Vitamin D Depletion

• Reduced intestinal calcium and phosphate absorption
• Serum calcium begins to fall (often still within normal range due to compensatory mechanisms)

Stage 2: Secondary Hyperparathyroidism

• Parathyroid glands detect reduced serum calcium
• PTH secretion increases to maintain normocalcaemia
• PTH actions:
  • Stimulates renal 1α-hydroxylase (attempting to maximise 1,25(OH)₂D production from limited 25(OH)D stores)
  • Increases renal calcium reabsorption (distal tubule)
  • Increases bone resorption (osteoclast activation)
  • Increases renal phosphate excretion (inhibits proximal tubular phosphate reabsorption via suppression of NPT2a/NPT2c transporters)

Stage 3: Hypophosphataemia

• PTH-mediated phosphaturia causes serum phosphate to fall
• Calcium often normalises (PTH-mediated bone resorption and renal retention)
• Calcium × Phosphate product falls below mineralisation threshold

Stage 4: Defective Mineralisation

• Osteoblasts continue producing osteoid matrix
• Insufficient calcium and phosphate for hydroxyapatite deposition
• Osteoid accumulates as unmineralised "seams" around bone
• Alkaline phosphatase rises (marker of frustrated osteoblast activity)
• Bone becomes structurally weak despite normal or increased volume

Stage 5: Clinical Osteomalacia

• Bone pain (periosteal stretching from unmineralised osteoid)
• Proximal myopathy (direct VDR effects on muscle)
• Increased fracture risk (stress fractures → pseudofractures)
• Skeletal deformity (in severe, longstanding cases)

FGF23-Mediated Hypophosphataemic Osteomalacia

In conditions like tumor-induced osteomalacia and X-linked hypophosphataemia, elevated FGF23 causes:

• Inhibition of renal phosphate reabsorption (via NPT2a/NPT2c suppression)
• Suppression of renal 1α-hydroxylase (reduced 1,25(OH)₂D production)
• Stimulation of renal 24-hydroxylase (increased vitamin D catabolism)
• Result: Severe hypophosphataemia with inappropriately low/normal 1,25(OH)₂D despite low phosphate [17,18]

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4. Clinical Presentation

Symptoms

Cardinal Symptoms

1. Bone Pain (80-100% of symptomatic patients)

   • Diffuse, persistent, deep aching quality
   • Typically affects: lower back, pelvis, hips, ribs, legs
   • Worse with weight-bearing, improves with rest (but never fully resolves)
   • Often described as "deep tiredness in the bones"
   • Pain may be vague and difficult to localise
   • NOT relieved by simple analgesics (key differentiator from mechanical pain) [8]

2. Proximal Muscle Weakness (50-80%)

   • Difficulty rising from a chair without using arms
   • Difficulty climbing stairs (especially descending)
   • Difficulty squatting or getting up from floor
   • Waddling gait (trendelenburg gait from gluteal weakness)
   • May mimic polymyositis or neurological disease
   • Muscle pain may coexist (often called "rheumatic" complaints) [6]

3. General Symptoms

   • Fatigue and malaise (very common, often attributed to other causes)
   • Reduced physical function and mobility
   • Difficulty with activities of daily living

Associated Symptoms

• Bone tenderness (spontaneous or on pressure)
• Height loss (vertebral compression)
• Skeletal deformity (severe, longstanding cases)
• Dental problems (delayed tooth eruption in late-onset cases, dental abscesses)

Signs

Examination Findings

General Inspection:

• Antalgic gait or waddling gait
• Use of walking aids
• Kyphosis or skeletal deformity (severe cases)

Musculoskeletal Examination:

• Bone tenderness: Elicited by firm pressure on:
  • Sternum (highly specific finding)
  • Anterior tibia
  • Ribs
  • Pelvis
• Proximal muscle weakness:
  • Gower's sign (difficulty rising from floor, using hands to "climb up" legs)
  • Positive chair rise test (inability to stand from seated position without arm support)
  • Trendelenburg gait (hip drop on contralateral side during single-leg stance)
  • Reduced power in hip flexion, hip abduction, shoulder abduction

Skeletal Deformity (severe, chronic cases):

• Triradiate pelvis (protrusio acetabuli)
• Kyphosis or kyphoscoliosis
• Bowing of long bones (weight-bearing bones)
• Reduced height

Clinical Presentation by Underlying Cause

Red Flag Features

⚠️ Features requiring urgent assessment:

• Pathological fracture (minimal trauma fracture)
• Severe hypocalcaemia with tetany, paraesthesiae, or seizures
• Profound weakness affecting respiratory muscles or swallowing
• Rapid deterioration in mobility
• Features of underlying malignancy (weight loss, night sweats, mass)

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5. Differential Diagnosis

Primary Differentials

5.1 Osteoporosis

Key Distinguishing Features:

• Normal biochemistry (calcium, phosphate, ALP all normal)
• Painless until fracture occurs
• DEXA scan shows low bone mineral density (T-score ≤ -2.5)
• Risk factors: post-menopausal, corticosteroid use, family history
• No proximal myopathy

5.2 Primary Hyperparathyroidism

Key Distinguishing Features:

• Hypercalcaemia (unlike osteomalacia where calcium is low/normal)
• Elevated PTH (primary, not secondary)
• Phosphate typically low (PTH-mediated phosphaturia)
• ALP may be elevated (from high bone turnover)
• "Bones, stones, groans, and moans" presentation
• Parathyroid adenoma/hyperplasia on imaging

5.3 Paget's Disease of Bone

Key Distinguishing Features:

• Very high ALP (often 5-10x upper limit of normal)
• Normal calcium and phosphate (unless immobilised or malignant transformation)
• Typically affects single or few bones (skull, spine, pelvis, femur)
• Bone pain localised to affected areas
• X-ray: bone expansion, cortical thickening, mixed lytic/sclerotic pattern
• Older age group (typically over 55 years)

5.4 Multiple Myeloma

Key Distinguishing Features:

• Hypercalcaemia (from osteolytic lesions)
• Elevated ESR/CRP and anaemia
• Bone pain typically focal (lytic lesions)
• Bence-Jones protein in urine
• Skeletal survey: punched-out lytic lesions
• Bone marrow infiltration with plasma cells

5.5 Polymyositis/Dermatomyositis

Key Distinguishing Features:

• Elevated CK (creatine kinase)
• Normal ALP
• Normal bone biochemistry
• EMG/muscle biopsy abnormalities
• May have skin changes (dermatomyositis)
• No bone pain or tenderness

5.6 Polymyalgia Rheumatica

Key Distinguishing Features:

• Elevated ESR/CRP (inflammatory markers)
• Normal ALP (or mildly elevated from inflammation)
• Shoulder and pelvic girdle pain and stiffness
• Dramatic response to prednisolone (15-20 mg)
• Age typically over 60 years
• No bone tenderness

Comparative Biochemistry

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6. Investigations

First-Line Investigations

6.1 Biochemistry (Essential)

Vitamin D Status:

• 25-Hydroxyvitamin D [25(OH)D]: The definitive measure of vitamin D status
  • "Severe deficiency: less than 25 nmol/L (less than 10 ng/mL)"
  • "Deficiency: 25-50 nmol/L (10-20 ng/mL)"
  • "Insufficiency: 50-75 nmol/L (20-30 ng/mL)"
  • "Adequate: greater than 75 nmol/L (greater than 30 ng/mL)"
  • In osteomalacia, typically less than 25 nmol/L [1,2]

Calcium and Phosphate:

• Serum Calcium (corrected for albumin):
  • Often low-normal or low (2.0-2.2 mmol/L)
  • May be normal due to PTH compensation
  • Ionised calcium more accurate if available
• Serum Phosphate:
  • Characteristically low (less than 0.8 mmol/L)
  • Reflects PTH-mediated phosphaturia
  • Fasting sample preferred (phosphate affected by meals)

Alkaline Phosphatase (ALP):

• Elevated (often 2-5x upper limit of normal)
• Predominantly bone isoenzyme (differentiate from liver ALP if needed)
• Reflects osteoblast activity
• Highest in severe, longstanding disease
• Takes 3-6 months to normalise with treatment

Parathyroid Hormone (PTH):

• Elevated (secondary hyperparathyroidism)
• Typically 2-5x upper limit of normal
• Should fall after vitamin D repletion (if primary hyperparathyroidism, PTH remains high)

Additional Biochemistry:

• Renal function (eGFR, creatinine): Essential to detect CKD
• Liver function tests: Exclude hepatobiliary disease
• Bone-specific ALP (if available): More specific than total ALP

6.2 Urinary Investigations

24-Hour Urine:

• Calcium excretion: Usually low (less than 2.5 mmol/24h) due to reduced absorption and PTH effect
• Phosphate excretion: Elevated (PTH-mediated phosphaturia)
• Tubular reabsorption of phosphate (TRP): Reduced (less than 85%)
• Tubular maximum reabsorption of phosphate/GFR (TmP/GFR): Reduced (less than 0.8 mmol/L)

Spot Urine (if Fanconi syndrome suspected):

• Glucose (glycosuria with normal blood glucose)
• Protein (tubular proteinuria)
• Amino acids
• pH (renal tubular acidosis)

6.3 Imaging

Plain Radiographs:

Pathognomonic Findings:

• Looser's Zones (Pseudofractures):
  • Radiolucent bands perpendicular to cortex
  • Bilateral and symmetrical
  • "Common sites: femoral neck, pubic rami, ribs, scapula, clavicle, proximal ulna"
  • Represent stress fractures filled with unmineralised osteoid
  • Highly specific (90-95%) but not sensitive (present in only 20-30%) [7]

Other Radiological Features:

• Generalised osteopenia (difficult to distinguish from osteoporosis)
• Codfish vertebrae: Biconcave compression of vertebral bodies
• Triradiate pelvis: Protrusio acetabuli (severe cases)
• Loss of trabecular pattern
• Blurred cortical margins
• Coarsened trabeculae

DEXA Scan:

• May show normal or even increased bone mineral density (unmineralised osteoid contributes to density)
• Not diagnostic but helps exclude osteoporosis
• Z-score may be more informative than T-score

Second-Line Investigations

6.4 Advanced Biochemistry

When Aetiology Unclear or Hypophosphataemia Disproportionate:

• FGF23 (Fibroblast Growth Factor 23):

  • Elevated in tumor-induced osteomalacia, XLH, ADHR
  • C-terminal or intact assay (intact preferred)
  • "Normal range: less than 180 RU/mL (assay-dependent) [17,18]"

• 1,25-Dihydroxyvitamin D [1,25(OH)₂D]:

  • Low or inappropriately normal in FGF23-mediated disorders
  • Not routinely needed in straightforward vitamin D deficiency

Screening for Malabsorption:

• Coeliac serology: Tissue transglutaminase IgA, total IgA
• Faecal elastase: Pancreatic insufficiency
• Stool microscopy: Fat malabsorption (rarely done)

Myeloma Screen (if concern for multiple myeloma):

• Serum and urine protein electrophoresis
• Serum free light chains
• Full blood count (anaemia)
• ESR/CRP

6.5 Imaging for Underlying Cause

If Tumor-Induced Osteomalacia Suspected:

• MRI whole body or specific regions
• ⁶⁸Ga-DOTATATE PET/CT: Functional imaging (somatostatin receptor expression in phosphaturic mesenchymal tumours)
• FDG-PET/CT: May localise occult tumours
• Tumours often small (less than 2 cm) and difficult to locate [17]

6.6 Bone Biopsy with Tetracycline Labelling

Gold Standard for Diagnosis (rarely performed in clinical practice):

Indications:

• Atypical presentation
• Diagnostic uncertainty
• Research purposes
• Hypophosphatasia suspected

Technique:

• Double tetracycline labelling (oral tetracycline given at 2 time points, 10-14 days apart)
• Tetracycline binds to mineralisation front
• Trans-iliac crest bone biopsy (under local or general anaesthesia)
• Undecalcified histomorphometry

Histological Findings in Osteomalacia:

• Increased osteoid volume (greater than 2% of bone volume)
• Increased osteoid surface (greater than 15% of bone surface)
• Increased osteoid thickness (greater than 12 μm)
• Prolonged mineralisation lag time (greater than 100 days; normal less than 25 days)
• Reduced mineral apposition rate
• Wide unmineralised osteoid seams surrounding trabeculae

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7. Classification and Staging

Classification by Aetiology

Type I: Vitamin D Deficiency/Resistance

• Nutritional deficiency
• Malabsorption
• Lack of sunlight
• Vitamin D-dependent rickets type I or II

Type II: Hypophosphataemic

• Renal phosphate wasting (FGF23-mediated or Fanconi syndrome)
• Dietary phosphate deficiency
• Phosphate binders

Type III: Mineralisation Defect

• Hypophosphatasia
• Bisphosphonate-induced
• Fluorosis
• Aluminium toxicity

Severity Grading (Clinical)

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8. Management

8.1 Acute Management

Severe Symptomatic Hypocalcaemia (rare, but life-threatening):

Presentation: Tetany, perioral paraesthesiae, carpopedal spasm, seizures, QTc prolongation

Management:

1. IV Calcium Gluconate:

   • 10 mL of 10% calcium gluconate in 100 mL normal saline over 10 minutes
   • Followed by infusion: 10 ampoules (100 mL) in 1 L normal saline over 24 hours
   • Cardiac monitoring (risk of arrhythmia if given too rapidly)

2. Oral Calcium:

   • Commence high-dose oral calcium (1500-2000 mg elemental calcium daily in divided doses)

3. Vitamin D:

   • Start replacement concurrently
   • In severe hypocalcaemia with CKD, may need alfacalcidol (active form) for rapid effect

4. Magnesium Replacement (if low):

   • Hypomagnesaemia impairs PTH secretion and vitamin D metabolism
   • IV magnesium sulphate 8 mmol over 12 hours

5. Monitor:

   • Serum calcium every 4-6 hours initially
   • ECG (QTc interval)
   • Watch for hypercalcaemia during repletion ("hungry bone syndrome")

8.2 Vitamin D Replacement

Standard Protocol (Normal Renal Function, eGFR greater than 30)

Loading Dose (Rapid Repletion Phase):

Colecalciferol (Vitamin D₃) - Preferred:

• Regimen 1: 50,000 IU (1.25 mg) once weekly for 6 weeks (Total: 300,000 IU)
• Regimen 2: 20,000 IU (500 μg) three times weekly for 6-8 weeks (Total: 360,000-480,000 IU)
• Regimen 3: 3,000-5,000 IU daily for 12 weeks (Total: 250,000-420,000 IU)

Alternative:

• Ergocalciferol (Vitamin D₂): 50,000 IU weekly for 8 weeks (less preferred; shorter half-life)
• Intramuscular (if compliance concern or severe malabsorption): 300,000 IU IM as single dose

Aim: Achieve 25(OH)D greater than 75 nmol/L

Maintenance Dose (Lifelong):

• Standard: 800-2,000 IU (20-50 μg) daily
• Higher risk groups (obesity, malabsorption, dark skin): 2,000-4,000 IU daily
• Elderly/institutionalised: Consider 4,000 IU daily or 20,000 IU weekly

Modified Protocol for Chronic Kidney Disease (eGFR less than 30)

CKD Stage 3-5 (Not on Dialysis):

• Impaired 1α-hydroxylation in kidney
• Option 1: High-dose colecalciferol (as above) plus alfacalcidol 0.25-1 μg daily
• Option 2: Paricalcitol (synthetic vitamin D analogue) 1-2 μg daily
• Avoid calcifediol in severe CKD
• Monitor: Calcium and phosphate weekly initially (risk of hypercalcaemia)
• Specialist endocrinology/nephrology input recommended [14]

Dialysis Patients:

• Active vitamin D analogues required: Alfacalcidol 0.5-2 μg daily or Calcitriol 0.25-0.5 μg daily
• IV Paricalcitol 1-5 μg three times weekly (with dialysis sessions)

Calcium Supplementation

Indications:

• Dietary calcium intake less than 700 mg/day
• Severe malabsorption
• During initial vitamin D replacement (prevent "hungry bone" hypocalcaemia)

Dose:

• Calcium carbonate (40% elemental calcium): 1-1.5 g elemental calcium daily in divided doses
• Calcium citrate (21% elemental calcium): Better absorbed, especially in achlorhydria/PPI use
• Ideally taken separately from iron, levothyroxine, bisphosphonates (absorption interference)

Duration:

• Usually 3-6 months, then review
• If dietary intake adequate and vitamin D replete, can discontinue

Phosphate Supplementation

Indications:

• Hypophosphataemic osteomalacia (tumor-induced, XLH, Fanconi syndrome)
• Not indicated in vitamin D deficiency osteomalacia (phosphate will correct with vitamin D)

Regimen:

• Sodium/potassium phosphate oral solution: 1-3 g elemental phosphorus daily in divided doses
• Given with calcitriol 0.5-1 μg daily (to enhance intestinal absorption and prevent secondary hyperparathyroidism)
• Multiple daily doses required (short half-life, GI side effects)

8.3 Treatment of Underlying Cause

8.4 Novel Therapies

Burosumab (Crysvita®):

• Fully human monoclonal antibody against FGF23
• Licensed for XLH and tumor-induced osteomalacia (when tumour unresectable)
• Dose: 1 mg/kg subcutaneous every 2-4 weeks (weight-based)
• Transformative for XLH: eliminates need for multiple daily phosphate doses, improves bone pain, mobility, and quality of life
• Expensive (£100,000+/year); specialist initiation
• Monitoring: Serum phosphate, calcium, vitamin D, PTH [17,18]

8.5 Monitoring During Treatment

Weeks 0-4:

• Check calcium at 1 month:
  • To detect "hungry bone" hypocalcaemia
  • To unmask primary hyperparathyroidism (if PTH remains elevated with normal/high calcium, consider primary rather than secondary hyperparathyroidism)

Months 3-6:

• Recheck biochemistry:
  • 25(OH)D (aim greater than 75 nmol/L)
  • Calcium, phosphate (should normalise)
  • ALP (takes 3-6 months to normalise; persistent elevation suggests alternative diagnosis or incomplete treatment)
  • PTH (should fall into normal range)

Clinical:

• Bone pain: Usually improves within 4-8 weeks
• Muscle weakness: Improves within 2-3 months
• Radiological healing: Pseudofractures take 6-12 months to heal
• Mobility: Gradual improvement; physiotherapy beneficial

Long-Term:

• Annual 25(OH)D measurement (ensure maintenance dose adequate)
• Annual calcium, phosphate, ALP if high-risk group
• Adjust maintenance dose to keep 25(OH)D greater than 75 nmol/L

8.6 Adjunctive Management

Physiotherapy:

• Graded exercise programme
• Strengthening exercises (especially proximal muscles)
• Gait re-education
• Falls prevention strategies

Analgesia:

• Bone pain often resistant to simple analgesics
• May require strong analgesics initially
• Improves as mineralisation restores (4-12 weeks)

Dietary Advice:

• Increase calcium-rich foods (dairy, fortified alternatives, leafy greens)
• Sun exposure guidance (10-15 minutes on arms/legs, 2-3 times weekly in summer)
• Vitamin D-rich foods (oily fish, egg yolks, fortified foods)

Fall Prevention:

• Home hazard assessment
• Walking aids if needed
• Muscle strengthening

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9. Complications

Skeletal Complications

Neuromuscular Complications

• Severe proximal myopathy: Loss of mobility, wheelchair dependence (reversible with treatment)
• Falls: Secondary to muscle weakness and gait instability
• Tetany and seizures: From severe hypocalcaemia (rare)

Dental Complications

• Delayed tooth eruption
• Dental abscesses (especially in XLH)
• Enamel hypoplasia

Cardiovascular (in Secondary Hyperparathyroidism)

• Vascular calcification
• Left ventricular hypertrophy
• Increased cardiovascular mortality (especially in CKD patients) [14]

Pregnancy-Related

• Pelvic deformity: May cause obstructed labour (rare in modern practice)
• Neonatal hypocalcaemia: If mother severely deficient during pregnancy

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10. Prognosis and Outcomes

With Treatment

Excellent Overall Prognosis:

• Complete recovery of bone strength expected within 6-12 months
• Pain relief typically within 4-8 weeks
• Muscle strength recovery within 2-4 months
• Pseudofractures heal within 6-12 months
• Biochemistry normalises within 3-6 months (ALP slowest to normalise)

Long-Term:

• No residual disability if treated adequately
• Normal life expectancy
• Lifelong maintenance vitamin D required if ongoing risk factors
• Annual monitoring recommended

Without Treatment

Progressive Deterioration:

• Increasing bone pain and disability
• Progressive muscle weakness
• Accumulation of pseudofractures
• Pathological fractures
• Skeletal deformity
• Wheelchair dependence
• Severe hypocalcaemia (risk of seizures, cardiac arrhythmia)

Special Populations

Tumor-Induced Osteomalacia:

• Curative if tumour completely resected (biochemistry normalises within days-weeks)
• Recurrence possible if incomplete resection [17]

X-Linked Hypophosphataemia:

• Lifelong treatment required
• Burosumab has transformed prognosis (improved pain, mobility, quality of life)
• Complications (enthesopathies, osteoarthritis) may still develop despite treatment [18]

CKD-Related:

• Prognosis tied to renal function
• Renal osteodystrophy complex (mixed picture)
• Requires specialist management [14]

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11. Prevention and Screening

Primary Prevention

Population-Level Strategies:

• Food fortification (milk, cereals, margarine) — widespread in North America, less so in Europe
• Public health advice on sun exposure (balance with skin cancer risk)
• Vitamin D supplementation programmes for high-risk groups

High-Risk Group Supplementation:

Screening Recommendations

Routine Population Screening: Not recommended (low yield, cost-ineffective)

Targeted Screening (Measure 25(OH)D):

Indicated in:

• Unexplained bone pain or proximal muscle weakness
• Fragility fractures
• Elevated ALP of unknown cause
• Chronic kidney disease (all stages)
• Malabsorption syndromes
• Pre-bariatric surgery and annually post-surgery
• Osteoporosis (before commencing bisphosphonates)
• Ethnic minorities with limited sun exposure
• Institutionalised elderly

Frequency:

• Annual for high-risk groups on maintenance therapy
• 6-12 monthly for malabsorption, CKD, post-bariatric
• One-off for low-risk groups with symptoms

Sunlight Exposure Guidance

• Sufficient exposure: 10-15 minutes of sun on arms and legs, 2-3 times weekly, between April-September (in UK)
• Latitude effect: At latitudes above 35°, vitamin D synthesis essentially ceases November-March
• Skin type: Darker skin requires 5-10x longer exposure
• Sunscreen: SPF 15+ blocks greater than 95% of vitamin D synthesis
• Through glass: No vitamin D synthesis (UV-B filtered)

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12. Evidence and Guidelines

Key Guidelines

Landmark Evidence

1. Christakos et al. (2020) - Vitamin D and Bone

• Comprehensive review of vitamin D metabolism and skeletal effects
• Primary role of 1,25(OH)₂D is increasing intestinal calcium absorption for bone mineralisation
• Direct and indirect effects on bone tissue [1]

2. Bikle DD (2012) - Vitamin D and Bone

• Demonstrated that rickets/osteomalacia can be corrected by calcium/phosphate supplementation alone (proving primacy of indirect effects)
• VDR-null mice rescued by high-calcium diet
• However, direct skeletal effects important for bone quality [2]

3. Florenzano et al. (2021) - Tumor-Induced Osteomalacia

• FGF23-secreting phosphaturic mesenchymal tumours
• Diagnosis requires high index of suspicion and systematic imaging approach
• Surgical resection curative; burosumab effective for inoperable cases [17]

4. Haffner et al. (2019) - X-Linked Hypophosphataemia Clinical Practice Recommendations

• European consensus on XLH diagnosis and management
• PHEX gene mutation leads to elevated FGF23
• Burosumab transforms outcomes compared to conventional phosphate/calcitriol therapy [18]

5. Francis RM et al. (2013) - National Osteoporosis Society Guideline

• Established UK standard loading regimen: 300,000 IU colecalciferol over 6-10 weeks
• Safe and effective for rapid vitamin D repletion
• No risk of toxicity with this protocol [19]

6. Khan et al. (2007) - Vitamin D Deficiency and Secondary Hyperparathyroidism in CKD

• Very high prevalence (greater than 80%) of vitamin D deficiency in CKD patients
• Secondary hyperparathyroidism leads to renal osteodystrophy
• Early detection and treatment crucial [14]

7. Clarke et al. (1995) - Osteomalacia Associated with Adult Fanconi Syndrome

• 11 patients with Fanconi syndrome and osteomalacia
• 8/11 had monoclonal disorders (myeloma, lymphoma)
• Responded well to calcium, phosphate, and vitamin D replacement
• Do not necessarily require active vitamin D [15]

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13. Patient and Layperson Explanation

What is Osteomalacia?

Osteomalacia means "soft bones". Think of bone as being like reinforced concrete — it needs both a steel framework (protein called collagen) and concrete (calcium minerals). In osteomalacia, your body makes the framework normally, but cannot fill it with enough calcium "concrete". The result is bones that are bendy and rubbery instead of strong and hard.

Is it the Same as Osteoporosis?

No, they are different conditions:

• Osteoporosis is "brittle bones" — like having less concrete altogether, but what you have is normal quality. It doesn't cause pain until you break something.
• Osteomalacia is "soft bones" — you have plenty of framework but not enough hardening mineral. It causes constant deep aching pain in your bones, even without breaking them.

Why Do I Have It?

The most common cause is severe lack of Vitamin D. You need vitamin D to absorb calcium from your food. Vitamin D comes from:

• Sunlight on your skin (the main source)
• Food (oily fish, eggs, fortified milk)
• Supplements

You might have osteomalacia because:

• You don't get enough sunlight (housebound, covering clothing, dark skin in northern countries)
• Your diet is low in vitamin D
• Your body can't absorb vitamin D properly (bowel disease, weight loss surgery)
• You have kidney disease (kidneys activate vitamin D)

What are the Symptoms?

• Bone pain: Deep, aching pain that never really goes away, especially in your back, hips, and legs
• Muscle weakness: Difficulty getting out of a chair, climbing stairs, or getting off the floor
• Tiredness: Feeling constantly exhausted
• Bone tenderness: Pain when pressing on your breastbone or shin

How is it Diagnosed?

A blood test showing:

• Very low vitamin D
• Low phosphate
• High alkaline phosphatase (a marker showing your bones are trying to repair)

Sometimes X-rays show "stress fractures" in your bones.

How is it Treated?

The good news is that osteomalacia is completely curable.

Treatment involves:

1. High-dose Vitamin D for 6-8 weeks to "fill up your tank" rapidly
2. Maintenance dose of vitamin D for life (a small daily tablet or weekly dose)
3. Calcium tablets if you're not getting enough from your diet
4. Treating the underlying cause (e.g., bowel disease, kidney disease)

Will I Recover?

Yes, fully. Most people notice:

• Pain improves within 4-8 weeks
• Strength returns within 2-3 months
• Full recovery within 6-12 months

Your bones will harden completely, and you'll regain normal strength. However, you'll usually need to continue taking vitamin D supplements to prevent it coming back.

What Happens if it's Not Treated?

Without treatment, the condition gets progressively worse:

• Increasing pain and disability
• Broken bones from minimal injury
• Muscle weakness leading to wheelchair dependence
• In rare cases, seizures from very low calcium

How Can I Prevent It?

• Sunlight: Try to get 10-15 minutes of sun on your arms and legs a few times a week in summer (without sunscreen)
• Diet: Eat oily fish (salmon, mackerel), eggs, fortified cereals and milk
• Supplements: If you're over 65, housebound, or have dark skin, take a daily vitamin D supplement (800-1,000 units)

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14. Examination Focus

Common MRCP/FRACP Exam Questions

1. Biochemistry Pattern Recognition:

• Question: "A 68-year-old woman presents with bone pain. Calcium 2.1 mmol/L, Phosphate 0.6 mmol/L, ALP 450 U/L. What is the diagnosis?"
• Answer: Osteomalacia (likely vitamin D deficiency). Low phosphate + high ALP + bone pain = osteomalacia. Check 25(OH)D and PTH.

2. Radiology:

• Question: "What are Looser's zones and where are they seen?"
• Answer: Looser's zones (pseudofractures) are radiolucent bands perpendicular to the cortex, representing stress fractures filled with unmineralised osteoid. Seen in osteomalacia. Common sites: femoral neck, pubic rami, ribs, scapula.

3. Differential Diagnosis:

• Question: "How do you distinguish osteomalacia from osteoporosis biochemically?"
• Answer:
  • Osteomalacia: ALP elevated, vitamin D low, phosphate low
  • Osteoporosis: All biochemistry normal (calcium, phosphate, ALP, vitamin D)

4. Treatment:

• Question: "How do you treat vitamin D deficiency osteomalacia?"
• Answer:
  • Loading: Colecalciferol 50,000 IU weekly for 6 weeks (or equivalent)
  • Maintenance: 800-2,000 IU daily lifelong
  • Add calcium if dietary intake inadequate
  • Check calcium at 1 month, full biochemistry at 3 months

5. Renal Osteomalacia:

• Question: "Which form of vitamin D should be used in CKD Stage 5?"
• Answer: Alfacalcidol or calcitriol (active forms). The kidney cannot perform 1α-hydroxylation in advanced CKD, so the active hormone must be given. Colecalciferol alone is insufficient.

6. Proximal Myopathy:

• Question: "An elderly woman presents with difficulty rising from a chair and a waddling gait. What vitamin deficiency might explain this?"
• Answer: Vitamin D deficiency. Causes proximal myopathy due to VDR expression in muscle tissue. Check 25(OH)D, calcium, phosphate, ALP, PTH.

7. Tumor-Induced Osteomalacia:

• Question: "A 45-year-old develops severe hypophosphataemia and osteomalacia with normal 25(OH)D. What is the likely diagnosis and key investigation?"
• Answer: Tumor-induced osteomalacia (TIO). Phosphaturic mesenchymal tumour secreting FGF23. Check serum FGF23 (elevated). Imaging: ⁶⁸Ga-DOTATATE PET/CT to localise tumour.

Viva Points

Opening Statement: "Osteomalacia is a metabolic bone disease characterised by defective mineralisation of bone, resulting in accumulation of unmineralised osteoid. It is the adult equivalent of rickets. The most common cause is severe vitamin D deficiency, but it can also result from hypophosphataemia due to renal phosphate wasting."

Key Facts to Mention:

• Epidemiology: Common in elderly, dark-skinned populations at northern latitudes, malabsorption syndromes
• Pathophysiology: Low vitamin D → reduced calcium/phosphate absorption → secondary hyperparathyroidism → phosphaturia → low Ca×PO₄ product → defective mineralisation
• Clinical triad: Bone pain + proximal myopathy + bone tenderness
• Biochemistry: Low 25(OH)D, low phosphate, high ALP, elevated PTH
• Radiology: Looser's zones (pathognomonic)
• Treatment: Colecalciferol loading (300,000 IU over 6 weeks) then maintenance (800-2,000 IU daily)
• Prognosis: Excellent — complete recovery expected within 6-12 months

Why is ALP Elevated? "Alkaline phosphatase is an enzyme produced by osteoblasts. In osteomalacia, osteoblasts are highly active, attempting to mineralise bone, but mineralisation is defective due to inadequate calcium and phosphate. The frustrated osteoblast activity results in large amounts of ALP being released into the circulation. It reflects bone formation activity, not mineralisation success."

Proximal Myopathy - Why? "Vitamin D receptors are abundantly expressed in skeletal muscle, particularly type II (fast-twitch) muscle fibres which predominate in proximal muscles. Vitamin D is essential for muscle protein synthesis, calcium handling in muscle cells, and mitochondrial function. Deficiency causes myopathy with weakness, reduced power, and muscle pain. This is independent of the bone disease."

How to Confirm Diagnosis if Uncertain? "The gold standard is iliac crest bone biopsy with double tetracycline labelling. Tetracycline binds to the mineralisation front. In osteomalacia, you see wide unmineralised osteoid seams (greater than 12 μm), increased osteoid volume (greater than 2%), and prolonged mineralisation lag time (greater than 100 days; normal less than 25 days). However, this is rarely needed in clinical practice — the biochemical picture is usually diagnostic."

Common Mistakes

❌ Failing to distinguish osteomalacia from osteoporosis

• Remember: Osteomalacia has high ALP; osteoporosis has normal biochemistry

❌ Using calcitriol (1,25(OH)₂D) for simple vitamin D deficiency

• Use colecalciferol (vitamin D₃) for deficiency
• Reserve calcitriol/alfacalcidol for CKD only

❌ Not checking calcium at 1 month after starting treatment

• Risk of unmasking primary hyperparathyroidism
• Risk of "hungry bone" hypocalcaemia

❌ Missing tumor-induced osteomalacia

• If hypophosphataemia is severe and vitamin D is normal, think FGF23-mediated disease
• Check serum FGF23

❌ Attributing proximal myopathy to neurological disease

• Always check vitamin D in unexplained proximal weakness
• CK is normal in vitamin D myopathy (elevated in polymyositis)

Model Answer: "Describe Your Approach to a Patient with Suspected Osteomalacia"

"I would approach this systematically:

History: I would ask about bone pain (site, duration, nature), muscle weakness (difficulty with stairs, rising from chair), falls, fractures. I would explore risk factors: sunlight exposure, dietary vitamin D and calcium intake, ethnicity, malabsorption symptoms, renal disease, medications (anticonvulsants, tenofovir).

Examination: I would look for bone tenderness (sternum, tibia), proximal muscle weakness (chair rise test, gait assessment), skeletal deformity.

Investigations: First-line would be 25(OH)D (the definitive measure of vitamin D status), serum calcium (corrected), phosphate, alkaline phosphatase, PTH, renal function. I would expect to find very low 25(OH)D (less than 25 nmol/L), low phosphate, elevated ALP, and elevated PTH (secondary hyperparathyroidism). Plain X-rays might show Looser's zones (pseudofractures).

Further investigations would depend on findings: if vitamin D is normal but phosphate very low, I would check FGF23 (tumor-induced osteomalacia, XLH). I would screen for malabsorption if clinically indicated (coeliac serology).

Management: If confirmed vitamin D deficiency osteomalacia, I would initiate colecalciferol loading (50,000 IU weekly for 6 weeks), followed by maintenance 800-2,000 IU daily. I would add calcium supplementation if dietary intake is inadequate. I would check calcium at 1 month (to detect primary hyperparathyroidism or hungry bone syndrome) and full biochemistry at 3 months (expect normalisation of phosphate, ALP, PTH).

I would counsel on sun exposure, dietary sources, and the excellent prognosis — complete recovery expected within 6-12 months. I would arrange physiotherapy for proximal muscle strengthening and falls prevention."

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15. References

Primary Sources

1. Christakos S, Li S, DeLa Cruz J, Verlinden L, Carmeliet G. Vitamin D and Bone. Handb Exp Pharmacol. 2020;262:47-63. doi:10.1007/164_2019_338

2. Bikle DD. Vitamin D and bone. Curr Osteoporos Rep. 2012;10(2):151-159. doi:10.1007/s11914-012-0098-z

3. Bhan A, Rao AD, Rao DS. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321-331. doi:10.1016/j.ecl.2010.02.001

4. Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res. 2010;25(2):305-312. doi:10.1359/jbmr.090728

5. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22(4):477-501. doi:10.1210/edrv.22.4.0437

6. Ceglia L, Harris SS. Vitamin D and its role in skeletal muscle. Calcif Tissue Int. 2013;92(2):151-162. doi:10.1007/s00223-012-9645-y

7. Chalmers J, Conacher WD, Gardner DL, Scott PJ. Osteomalacia: a common disease in elderly women. J Bone Joint Surg Br. 1967;49(3):403-423.

8. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int. 2000;66(6):419-424. doi:10.1007/s002230010085

9. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. doi:10.1056/NEJMra070553

10. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144PA:138-145. doi:10.1016/j.jsbmb.2013.11.003

11. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab. 2001;86(3):1212-1221. doi:10.1210/jcem.86.3.7327

12. Md Isa Z, Mohd Nordin NR, Mahmud MH, Hashim S. An Update on Vitamin D Deficiency Status in Malaysia. Nutrients. 2022;14(3):567. doi:10.3390/nu14030567

13. Stein EM, Strain G, Sinha N, et al. Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study. Clin Endocrinol (Oxf). 2009;71(2):176-183. doi:10.1111/j.1365-2265.2008.03470.x

14. Khan S. Vitamin D deficiency and secondary hyperparathyroidism among patients with chronic kidney disease. Am J Med Sci. 2007;333(4):201-207. doi:10.1097/MAJ.0b013e31803bb129

15. Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA. Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clin Endocrinol (Oxf). 1995;43(4):479-490. doi:10.1111/j.1365-2265.1995.tb02621.x

16. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67(2):373-378. doi:10.1210/jcem-67-2-373

17. Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-Induced Osteomalacia. Calcif Tissue Int. 2021;108(1):128-142. doi:10.1007/s00223-020-00691-6

18. Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435-455. doi:10.1038/s41581-019-0152-5

19. Francis RM, Aspray TJ, Fraser WD, et al. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. National Osteoporosis Society. 2018.

20. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385

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